Cyclosporine (CsA) has had a positive impact on graft survival in organ transplantation. However, a significant percent of patients receiving this immunosuppressive agent develop nephrotoxicity. CsA is known to cause acute renal vasoconstriction and reduction in glomerular filtration as well as a more chronic form of renal dysfunction characterized by arteriolopathy, glomerulosclerosis, interstitial fibrosis and tubular atrophy. While the mechanism is not understood, evidence suggests that progressive CsA nephropathy may have a vascular basis. The proposed studies will examine this promise. The purpose of the proposal is, first, to determine the mechanism of CsA-induced vasoconstriction; second, to determine if continuous CsA-related vasoconstriction and direct endothelial or smooth muscle cell toxicity leads to fixed alterations in renovascular reactivity including loss of autoregulation, and third, to determine if the loss of autoregulation causes changes in glomerular and post-glomerular hemodynamics that accelerate glomerular-injury and promote tubulointerstitial damage. The mechanism of vasoconstriction will be examined in isolated rat arterial vessels and endothelial cells in which CsA stimulation or suppression of endothelial and smooth muscle vasoactive factors will be assessed and in intact rats where the role of renal adrenergic nerves will be determined. The role of vasoconstriction and CsA vasotoxicity in altered vascular reactivity will be examined in isolated rat arterial vessels in which CsA- dependent mitogenic activity and autoregulatory capacity will be assessed. The effect of altered vascular reactivity and loss of autoregulation on glomerular and post-glomerular hemodynamics and vascular integrity will be determined with rat micropuncture studies and measurements of post- glomerular capillary permeability. The goal of this proposal is to develop an understanding of the mechanism and consequences of CsA vasotoxicity that can serve as a basis for preventive therapy.